Self/nonself recognition is a fundamental aspect of life. The evolution of cellular cooperation that led to tissues, organs and multicellular organisms is thought to have required the development of robust mechanisms of self/nonself recognition, or allorecognition, to preclude exploitation by genetically dissimilar competitors. The social amoeba, Dictyostelium discoideum, is an excellent model system in which cell adhesion, signaling and tissue formation during development have been studied extensively and for which powerful molecular genetic tools have been developed. We propose that cells integrate adhesion and communication during D. discoideum development to optimize cellular cooperation through a process of allorecognition that favors communal sporulation between genetically related individuals. Wild isolates of D. discoideum display cooperative behavior that is directly proportional to their genetic relatedness and we have uncovered a family of proteins that may form part of the molecular basis for this cooperation. This idea is based on our findings that the adhesion protein LagC1 and the related protein LagB1 are required for the cellular cooperation needed to integrate cells into a multicellular tissue, their genes are co-regulated, both display evidence of positive or balancing selection, suggestive of adaptive evolution, and their sequence polymorphism correlates well with allorecognition. Genes of the LagC1 type are abundant and polymorphic in the human genome as well, suggesting that the mechanisms we find in Dictyostelium would be relevant and applicable to human development and innate immunity. We hypothesize that highly polymorphic membrane proteins may mediate allorecognition in general, and that the specific proteins LagB1 and LagC1 interact functionally to mediate allorecognition through allele-specific intercellular adhesion and signaling, thus favoring cooperative sporulation of genetically similar individuals. To test these hypotheses, we will search the Dictyostelium genome for genes that encode polymorphic transmembrane proteins and test their correlation with allorecognition (segregation) between wild strains. We will further study the role of the most correlated proteins in allorecognition using mutagenesis and gene replacement approaches following the example of studying the specific roles of LagB1 and LagC1 in the process. PUBLIC HEALTH RELEVANCE: Allorecognition (self/nonself recognition) in humans is mainly achieved by our adaptive immune system whose high efficiency obscures the potential activity of other mechanisms, such as innate immunity systems that are conserved between numerous species. Nevertheless, there are groups of patients in which the adaptive immune system is failing due to AIDS or immune suppressive treatments in cases of cancer, transplantation or autoimmune diseases. The protein family we are studying is well represented in the human genome but little is known about its function in allorecognition, so studies in a simple model system such as Dictyostelium discoideum would allow us to understand their function using high-resolution methods that are either unavailable or hard to implement in humans.